PROJECT SUMMARY/ABSTRACT This is an application for a Mentored Patient-Oriented Research Career Development Award (K23). The goal of the proposed project is to provide the candidate with skills necessary to develop an independent research program dedicated to the development of neuroimaging biomarkers in Progressive Supranuclear Palsy (PSP) and other Alzheimer disease-related dementias. To facilitate this long-term career goal the candidate will: 1) identify multimodal (volumetric, structural and functional connectivity) magnetic resonance imaging (MRI) differences among 3 PSP subtypes (PSP-Richardson syndrome (PSP-RS), PSP-Speech/Language Disorder (PSP-SL), and PSP-Corticobasal syndrome (PSP-CBS)) as delineated in the recently revised PSP diagnostic criteria, and 2) examine the associations between these imaging features with cross-sectional characteristics and 1-year clinical change. The candidate proposes a comprehensive training plan, combining formal coursework, meetings and tutorials overseen by his mentors, participation in applied training experiences, and involvement in seminars and workshops. Specific training goals include: 1) training in neuroimaging methods and image analysis; 2) advanced training in experimental study design and statistical analysis; 3) advanced training in clinical trials methodology; 4) training in manuscript preparation, grant writing and leadership capability; and 5) continued training in the responsible conduct of research. The training plan will be implemented in coordination with a research project based on preliminary data collected by the applicant. The primary hypotheses to be examined are: 1) In PSP-RS, there will be greater structural and functional connectivity disruptions in bilateral dorsal midbrain and frontostriatal gray matter compared with other PSP subtypes, and significant associations between baseline bilateral diffusion tensor imaging (DTI) dorsal midbrain/resting state-fMRI (rs-fMRI) frontostriatal connectivity and executive function; 2) In PSP-SL, there will be greater structural and functional connectivity disruptions in the dominant inferior frontal cortex and its subcortical speech network connections, and significant associations between baseline DTI and rs-fMRI measures in the dominant inferior frontal lobe and language function; and 3) In PSP-CBS, there will be greater structural and functional connectivity disruptions in the parietal lobe-dorsolateral striatum network contralateral to the most affected side, and significant associations between baseline DTI and rs-fMRI measures in the parietal lobe-dorsolateral striatum and praxis. Results from this research will be used to develop a R01 research proposal that will facilitate the candidate?s transition to an independent researcher.